Cancers of the bone, both primary bone cancers and those that have metastasized to bone (bone metastases), involve complex molecular processes and have been difficult to treat. Bone metastases, a frequent consequence of common malignancies such as breast, lung and prostate cancer, are often associated with severe bone pain and pathological fractures due to increased bone fragility. Primary bone cancers (e.g., osteogenic sarcoma) present treatment challenges, and patients often require limb amputation and/or radiation therapy. In the bone microenvironment, as it is currently understood, metastasized cancer cells produce activating factors (e.g., PTHrP) that stimulate osteoclast-mediated bone resorption. Bone-derived growth factors (e.g., TGF-β and IGF1) are subsequently released, promoting cancer-cell proliferation and the amplification of a cycle that produces net osteolytic (bone destructive) consequences.
The development of new therapeutic agents for treating cancers of the bone, preferably agents that act directly and potently to inhibit bone breakdown and tumor growth would be highly desirable.
Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. It binds to a FK506-binding protein, FKBP12, with high affinity to form a rapamycin:FKBP complex. Reported Kd values for that interaction are as low as 200 pM. The rapamycin:FKBP complex binds with high affinity to the large cellular protein, FRAP, to form a tripartite, [FKBP:rapamycin]:[FRAP], complex. In that complex rapamycin can be viewed as a dimerizer or adapter to join FKBP to FRAP. Formation of the complex is associated with rapamycin's various biological activities.
Rapamycin is a potent immunosuppressive agent and is used clinically to prevent rejection of transplanted organs. Rapamycin and/or its analogs, AP23573 (ARIAD), CCI 779 (Wyeth) and SDZ Rad (“RAD001”, Novartis) are promising agents for treating certain cancers, for immune suppression and/or for helping to decrease the incidence of restenosis following interventional cardiology. Rapamycin has also been shown to have activity as an antifungal agent, in the experimental allergic encephalomyelitis model (a model for multiple sclerosis), in the adjuvant arthritis model (for rheumatoid arthritis), in inhibiting the formation of IgE-like antibodies, and for treating or preventing lupus erythematosus, pulmonary inflammation, insulin dependent diabetes mellitus, adult T-cell leukemia/lymphoma, and smooth muscle cell proliferation and intimal thickening following vascular injury. See e.g. published US Patent application 2001/0010920.
Rapamycin's potential for providing relief from such an important swath of cruel diseases has stimulated the search for rapamycin analogs with improved therapeutic index, pharmacokinetics, ease or economy of production or formulation, etc. The resulting investigation by industrial and academic researchers has led to the exploration of materials and methods for effecting chemical transformations of rapamycin, including reductions of ketones, demethylations, epimerizations, various acylations and alkylations of hydroxyls, etc.
A large number of structural variants of rapamycin have now been reported, typically arising as alternative fermentation products and/or from synthetic efforts. For example, the extensive literature on analogs, homologs, derivatives and other compounds related structurally to rapamycin (“rapalogs”) include, among others, variants of rapamycin having one or more of the following modifications relative to rapamycin: demethylation, elimination or replacement of the methoxy at C7, C42 and/or C29; elimination, derivatization or replacement of the hydroxy at C13, C43 and/or C28; reduction, elimination or derivatization of the ketone at C14, C24 and/or C30; replacement of the 6-membered pipecolate ring with a 5-membered prolyl ring; and alternative substitution on the cyclohexyl ring or replacement of the cyclohexyl ring with a substituted cyclopentyl ring. Additional historical information is presented in the background sections of U.S. Pat. Nos. 5,525,610; 5,310,903 and 5,362,718. See also U.S. Pat. No. 5,527,907. Materials and methods have even been developed for the remarkably effective and selective epimerization of the C-28 hydroxyl group (WO 01/14387). See also U.S. Ser. No. 10/357,152 WO 03/064383 and WO 05/16252 for additional background on methods and materials for the preparation and use of rapamycin analogs containing various phosphorus-containing moieties.
New rapalogs with attractive physicochemical or functional characteristics relative to rapamycin, e.g., in therapeutic index, bioavailability, pharmacokinetics, stability, tissue distribution, etc., would also be of interest for a variety of pharmaceutical uses including among others bone cancers and other bone disorders involving bone resorption.
The three rapalogs currently in clinical development for cancer include two with conventional structural modifications, i.e., acylation or alkylation of the O at C-43 [CCI 779 and SDZ RAD, respectively; see e.g., Yu et al., Endocrine Related Cancer (2001) 8, 249-258; Geoerger et al., Cancer Res. (2001) 61 1527-1532) and Dancey, Hematol Oncol Clin N Am 16 (2002):1101-1114] and one with a rather unusual phosphine oxide substituent at that site (AP23573).
The invention described below represents a rather dramatic departure in the design of new rapalogs based on the incorporation of more elaborate phosphorus-containing moieties.